EP2741734A1 - Method for producing and monitoring oral active ingredient films - Google Patents

Method for producing and monitoring oral active ingredient films

Info

Publication number
EP2741734A1
EP2741734A1 EP12735126.0A EP12735126A EP2741734A1 EP 2741734 A1 EP2741734 A1 EP 2741734A1 EP 12735126 A EP12735126 A EP 12735126A EP 2741734 A1 EP2741734 A1 EP 2741734A1
Authority
EP
European Patent Office
Prior art keywords
base
radiation
active ingredient
printing
coated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP12735126.0A
Other languages
German (de)
French (fr)
Other versions
EP2741734B1 (en
Inventor
Sebastian Braun
Armin Breitenbach
Ralf Schliephacke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tesa SE
Tesa Labtec GmbH
Original Assignee
Tesa SE
Labtec GmbH
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Application filed by Tesa SE, Labtec GmbH filed Critical Tesa SE
Publication of EP2741734A1 publication Critical patent/EP2741734A1/en
Application granted granted Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the invention relates to a process for the preparation and control of oral drug films.
  • ODFs Oral Dissolvable Films
  • the film is made using hydrophilic polymers such as cellulose or maltodextrin.
  • the active ingredient may be dissolved, emulsified or dispersed in the matrix from the polymers. He can also be complex. Furthermore, the active substance can be applied to the matrix in a further layer. Importantly, the polymers quickly dissolve on the tongue or in the oral cavity, releasing the drug when it comes in contact with a liquid.
  • the absorption of drugs in the oral cavity occurs primarily through the buccal and sublingual mucosa.
  • the very good blood circulation of the oral mucosa is ensured by a dense network of capillaries.
  • the diffusion of an active substance into this network of microcirculation allows an immediate transition into the bloodstream.
  • Such films or the film strips have a limited areal extent, typically with a size between 1 cm 2 and 10 cm 2 and a film thickness of 20 to 500 ⁇ .
  • the ODFs in the form of oral hygiene strips have become more widespread.
  • the very valuable active ingredient is dosed and added as standard already in the first step, so that in all subsequent steps, the resulting entry and waste materials are contaminated with the drug. Unnecessary losses of the valuable active ingredient and very expensive cleaning and disposal work after production are the result. Furthermore, a complex intermediate product control is required in order to be able to monitor the homogeneous uniform distribution of the active ingredient in each work step.
  • From DE 34 23 328 A1 is known as a continuous printing process for the transfer of adhesives, which may contain active ingredients, the gravure and the screen printing process.
  • ODFs Another problem in the production of ODFs is that the mandatory control of the active ingredient content usually takes place as a destructive product test, that is, the individual ODF is analyzed for its constituents, comparing the detected active ingredient content with the predetermined active ingredient content. If a deviation is detected, this can lead to the loss of an entire batch.
  • a typical composition of an oral drug film looks like this:
  • Water-soluble film polymer such as Pharmacoat or Methocel (hydroxyporpyl methylcellulose) 40 to 50% by weight
  • Plasticizers such as glycerol 0 to 20% by weight
  • Fillers, dyes, flavorings and other additives 0 to 40% by weight
  • the object of the invention is to provide a process for the preparation and control of oral drug films, which leads by a precise manufacturing process and by an effective control method to the lowest possible loss of active ingredients and suppresses the variations in the active ingredient content in the oral drug films as possible.
  • the invention relates to a process for the preparation and control of oral drug films with a base to which a solution containing at least one drug is applied, comprising the steps:
  • the flexographic printing process is a continuous printing process, offers the required high precision and ensures the high uniformity in the transfer of active pharmaceutical ingredients on the base recipe train.
  • the simple structure of a flexographic printing unit makes it possible to realize a process-reliable coating process with minimal losses of ink quantities.
  • the order quantity can be determined by different design of the high-precision anilox roller and thus also enables the reliable uniformity of the order quantity.
  • flexographic printing is a process of direct high pressure.
  • the printing form is made of rubber or elastic photopolymeric plastic.
  • the inking of the printing plate by means of an etched or engraved anilox roller made of steel with chrome plating or ceramic (chromium oxide), the wells are filled directly with a chambered doctor blade or a fountain roller with ink.
  • the excess ink is scraped from the anilox roller with a squeegee or squeezed (in older machines) with a rubber roller.
  • the printing speed is 100 to 300 m / min in packaging printing.
  • the main field of application is packaging printing.
  • the printed base recipe web is wound up (after the measurement) and fed again to the one flexographic printing unit. This process can be carried out several times in succession until the desired amount of active ingredient has been applied.
  • the pressure does not have to be on the entire surface, a partial transfer of at least one drug-containing dye solution is also possible.
  • the proportion of active ingredient (s) in the at least one drug-containing dye solution is between 0.01 and 25 wt .-%, in particular 5 to 15 wt .-%.
  • the value of 25% by weight may also be exceeded, depending on the requirements, if it is necessary to achieve the desired effect.
  • the proportion of dye (s) in the at least one drug-containing dye solution is 0.01 and 10 wt .-%, in particular 1 to 5 wt .-%. However, the value of 10% by weight may also be exceeded, depending on the requirements, if it is necessary to achieve the desired effect. Dyes should only be used as those which are also authorized in medicinal products. Such dyes can be found, for example, in lists published by the Food and Drug Administration (FDA) under the name "Summary of Color Additives for Use in United States in Foods, Drugs, Cosmetics, and Medical Devices.” Among these dyes mentioned by name
  • the drying of the base receiving web coated on the base together with the printed active substance solution is preferably carried out continuously. Suitable continuous drying processes include hot air drying, infrared drying, high frequency drying and / or combinations of all processes.
  • the drying profile (temperature and time) is adjusted so that the lowest possible residual solvent content is achieved. Suitable temperatures are between 40 ° C and 150 ° C, suitable drying times of 1 to 30 minutes.
  • the determination of the active ingredient content is realized according to the invention by means of a dye addition in the active substance-containing printing ink solution and a physical transmission measuring method.
  • transmittance - With the transparency or transmittance - sometimes referred to as transmittance - which is usually given in%, the ratio of the incident on the back of a light-irradiated body light output is meant to the incident on the front light output.
  • the transmission is trimmed by reflection and absorption.
  • transmission is inventively extended to the effect that regardless of the type of radiation used, the loss of radiation during Passage through the base formulation layer together with color and active substance application is referred to as transmission.
  • the radiation source radiates through the base recipe web, along with the printed colored drug solution. Radiation losses occur during transmission, which can be detected on the opposite side of the web via a corresponding detector.
  • a zero measurement is first to be made, that is to say, the base formulation track printed with the desired concentration of active dye and dye (as a precaution, the actual active substance content should be confirmed by a second, different measuring method) is irradiated and the transmission value determined.
  • the currently measured transmission value is compared with the zero value. If the actual measured value deviates from the desired specification, it is possible to react immediately, for example by stopping the method in order to stop the error. In this way, the losses are effectively reduced.
  • a dye which absorbs the light radiation of a red light source can be contained in the active substance-containing printing ink solution. If a small amount of dye, ie at the same time printed active substance, the absorption of light is low and a larger amount of light is detected by a photocell, as if a high dye and thus drug amount would be printed.
  • the transmittance is directly dependent on the amount of dye (associated amount of active substance) and thus a direct contactless test method for determining the active ingredient content, without the test specimen must be destroyed.
  • control method is an optical method.
  • the individual sections of the oral active substance films are punched as lossless as possible after the coating of the base formulation on a substrate and the subsequent drying from the resulting web, either directly before the printing process or directly after the printing process.
  • the individual sections of the oral active substance films are punched as loss-free as possible.
  • the punching device consists of a rotary cutting roller and a counter-rotating counter-rotating roller, wherein the base receiving track is guided into the gap between the cutting roller and the counter-roller.
  • the base receiving web is located on a release film, which is guided over the counter roll. In the gap then the individual contours of the punched pieces are preferably punched through without punched grid in the web, if possible without violating the release film (this method is known under the name kiss-cut method and is characterized in that when punching the release film or not only marginally injured or punched).
  • the punching device consists of a lifting or flat punch, in which the base receiving track is conveyed.
  • a buffer may be provided to ensure a continuous progress of the process despite the bagged and thus actually discontinuous operation of the Hubstanze.
  • the individual sections of the oral drug films are advantageously air-tight and watertight sealed in a bag.
  • the invention are as radiation infrared radiation, visible light, ultraviolet radiation and / or radioactive radiation used.
  • the invention is not limited to the radiation sources mentioned, others are suitable for this purpose.
  • the radiation receiver oscillates in particular in the transverse direction of the base reception track.
  • the base receiving web is coated on a carrier film as backing, preferably made of polyethylene, which is guided through the process together with the base receiving web.
  • a carrier film as backing preferably made of polyethylene
  • Particularly preferred as backing is a film of polyester, most preferably of polyethylene terephthalate (PET).
  • the thickness of the release film is in particular between 60 and 150 ⁇ .
  • the thickness of the base receiving web is usually between 25 and 200 ⁇ m, in particular between 65 and 100 ⁇ m.
  • the width of the base receiving track is preferably between 20 and 35 mm, 30 mm are particularly advantageous.
  • the process is carried out continuously in one operation.
  • rolls can then be stored or delivered to a processor. If necessary, the rolls are unwound, and the inventive method begins with the printing of a dye solution containing at least one active substance by the Flexod jerk process on the top of the base formulation web.
  • Typical active ingredients are - without the claim of completeness to be raised in the context of the present invention: Antiallergic, antiarrhythmic, antibiotic, antidiabetic, antiepileptic, antihistaminic, antitussive, cardiotonic, diuretic, hypotensive, narcotic, neuro-muscular, sex hormones and vasopressors. These can also be used in mixtures depending on the therapeutically desired result.
  • the substances menthol known from oral hygiene strips can be used according to the invention as active ingredients, as well as other flavorings, flavors or fragrances, as used in the field of oral hygiene.
  • Typical polymers for forming the base formulation film are cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose and / or hydroxypropylcellulose and maltodextrin.
  • the polymers can be used individually or in any mixtures.
  • radiation sources light sources that emit in the desired wavelength range can be used.
  • radioactive lamps are also used.
  • a receiving unit serve photocells. With radioactive radiation, one or more Geiger counters suffice to detect the radiation.
  • the invention avoids excessive losses of active ingredient and the resulting complex cleaning and disposal work in case of defective production and the intermediate controls,
  • the process has a simple and compact machine structure and allows rapid conversion to other drug-containing inks, whereby a cross-contamination of different active ingredients can be avoided.
  • a flexographic printing machine was equipped with a chromium-plated anilox roller, the screen ruling 54 lines per cm, the depth of which is 40 ⁇ and their theoretical Schöpfvolumen 1 1, 7 cm 3 / m 2 .
  • the printing cylinder used was an EPDM-coated rubber roller.
  • An impression cylinder forms with the impression cylinder a nip in which the printing takes place according to the type of flexographic printing known to the person skilled in the art.
  • the base recipe web fed into the nip via the impression cylinder was an ODF base film roll 20 mm wide and 100 m long, whose major component is hydroxypropylmethyl cellulose.
  • the printing ink solution consisting of 4.4% by weight of hydroxypropylcellulose, 8.9% by weight of active substance, 2.3% by weight of blue dye and 84.4% by weight of ethanol is applied at a printing speed of 15 m / min printed on the base recipe track.
  • the printing unit is followed by a dryer unit in which the solvent is evaporated in the form of ethanol by convection drying.
  • the printed ribbon is then wound into a roll and printed three times in succession without retooling the flexo.
  • the transmission value decreases with an increase in the colorant and concomitantly the active ingredient concentration.
  • the transmission value is determined. Deviations from this outside the specified error tolerances are determined inline and thus immediately, so that an intervention in the process can be carried out as quickly as possible.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

Method for producing and monitoring oral active ingredient films with a base to which a solution containing at least one active ingredient is applied, the method comprising the steps: • metering and mixing the base formulation, • coating the base formulation onto a substrate, so that a strip results • if necessary, drying the base formulation strip coated on the substrate • printing a colorant solution containing at least one active ingredient onto the upper side of the base formulation strip according to the flexographic printing method, • drying the base formulation strip coated on the substrate together with the printed active ingredient solution, • penetrating the base formulation strip coated on the substrate together with the printed active ingredient solution from the upper and/or lower side by means of radiation from a radiation source, • measuring the transmission of the penetrating radiation by means of at least one reception unit on the opposite side of the base formulation strip coated on the substrate together with the printed active ingredient solution.

Description

Beschreibung  description
Verfahren zur Herstellung und Kontrolle von oralen Wirkstoff-Filmen Die Erfindung betrifft ein Verfahren zur Herstellung und Kontrolle von oralen Wirkstoff- Filmen. The invention relates to a process for the preparation and control of oral drug films.
Orale Wirkstoff-Filme (Englisch „Oral Dissolvable Films: ODFs") stellen eine vergleichsweise neue Technologie zur oralen Verabreichung von Wirkstoffen dar. Diese Filme sind hauchdünne, ein- oder mehrschichtige Polymerfilme, die den Mund sowohl zur Applikation als auch zur Wirkstoffabsorption nutzen. Oral Dissolvable Films (ODFs) are a relatively new technology for oral administration of drugs. These films are wafer-thin, single- or multi-layer polymer films that use the mouth for both application and drug absorption.
Der Film wird unter Verwendung von hydrophilen Polymeren wie Cellulose oder Maltodextrin hergestellt. Der Wirkstoff kann in der Matrix aus den Polymeren gelöst, emulgiert oder dispergiert vorliegen. Er kann auch komplex gebunden sein. Des Weiteren kann der Wirkstoff auf der Matrix in einer weiteren Schicht aufgebracht sein. Wichtig ist, dass sich die Polymere schnell auf der Zunge oder in der Mundhöhle auflösen und dabei den Wirkstoff freisetzen, wenn er mit einer Flüssigkeit in Kontakt kommt. The film is made using hydrophilic polymers such as cellulose or maltodextrin. The active ingredient may be dissolved, emulsified or dispersed in the matrix from the polymers. He can also be complex. Furthermore, the active substance can be applied to the matrix in a further layer. Importantly, the polymers quickly dissolve on the tongue or in the oral cavity, releasing the drug when it comes in contact with a liquid.
Die Absorption von Arzneistoffen in der Mundhöhle erfolgt in erster Linie über die bukkale und sublinguale Schleimhaut. Die sehr gute Durchblutung der Mundschleimhaut wird durch ein dichtes Netzwerk von Kapillaren gewährleistet. Die Diffusion eines Wirkstoffes in dieses Netzwerk der Mikrozirkulation ermöglicht einen unmittelbaren Übergang in den Blutkreislauf. The absorption of drugs in the oral cavity occurs primarily through the buccal and sublingual mucosa. The very good blood circulation of the oral mucosa is ensured by a dense network of capillaries. The diffusion of an active substance into this network of microcirculation allows an immediate transition into the bloodstream.
Derartige Filme beziehungsweise die Filmstreifen haben eine begrenzte flächenförmige Ausdehnung, typischerweise mit einer Größe zwischen 1 cm2 und 10 cm2 und eine Filmdicke von 20 bis 500 μηη. Größere Verbreitung haben die ODFs in Form von Mundhygienestreifen gefunden. Such films or the film strips have a limited areal extent, typically with a size between 1 cm 2 and 10 cm 2 and a film thickness of 20 to 500 μηη. The ODFs in the form of oral hygiene strips have become more widespread.
Herkömmliche Herstellverfahren für derartige ODFs umfassen die folgenden Arbeitsschritte: Conventional manufacturing methods for such ODFs include the following steps:
1 . Dosieren und Mischen der Basisrezeptur aus Cellulose oder Maltodextrin inklusive des Wirkstoffs 1 . Dosing and mixing of the base formulation of cellulose or maltodextrin including the active substance
2. Beschichtung der Masse auf eine Hilfsträgerfolie  2. Coating the mass onto a subcarrier film
3. Trocknung der auf Hilfsträgerfolie beschichteten Masse  3. Drying of the coated on subcarrier film mass
4. Schneiden und Wickeln von Mutterrollen  4. Cutting and winding mother rolls
5. Ablängen, Vereinzeln und Einsiegeln von ODFs in einen Siegelbeutel  5. Cut to length, singulate and seal ODFs into a sealed bag
Der sehr wertvolle Wirkstoff wird standardmäßig schon in dem ersten Arbeitsschritt dosiert und zugegeben, so dass in allen darauffolgenden Arbeitsschritten die anfallenden Einfahr- und Abfallmaterialien mit dem Wirkstoff behaftet sind. Unnötige Verluste von dem wertvollen Wirkstoff und sehr aufwändige Reinigungs- sowie Entsorgungsarbeiten nach der Herstellung sind die Folge. Des Weiteren ist eine aufwändige Zwischenproduktkontrolle erforderlich, um die homogene Gleichverteilung des Wirkstoffs bei jedem Arbeitsschritt überwachen zu können. The very valuable active ingredient is dosed and added as standard already in the first step, so that in all subsequent steps, the resulting entry and waste materials are contaminated with the drug. Unnecessary losses of the valuable active ingredient and very expensive cleaning and disposal work after production are the result. Furthermore, a complex intermediate product control is required in order to be able to monitor the homogeneous uniform distribution of the active ingredient in each work step.
Zum Aufbringen von Wirkstoffen in der Arzneimittelindustrie ist der Einsatz von Druckverfahren bekannt, und zwar vorrangig zum Markieren und Identifizieren von Pillen, Tabletten oder Kapseln. Dies kann der US 2009/026286 A1 oder der WO 2006/047695 A1 entnommen werden. Des Weiteren werden Bruchzonen auf Kapseln oder Tabletten mithilfe eines getakteten, das heißt nicht kontinuierlichen Druckverfahrens gekennzeichnet, wie die US 2007/0014852 A1 oder die WO 2006/058247 zeigen. Üblicherweise kommen Ink-Jet-Verfahren oder Tampondruckverfahren zur Anwendung. Die hierbei verwendeten Druckfarben beinhalten zumeist Wachse und/oder Fette oder Inhaltsstoffe, die die Kratzfestigkeit auf den Oberflächen erhöhen. Dies beschreibt die WO 2005/053599 A1 . For the application of active ingredients in the pharmaceutical industry, the use of printing processes is known, primarily for marking and identifying pills, tablets or capsules. This can be taken from US 2009/026286 A1 or WO 2006/047695 A1. Furthermore, fracture zones on capsules or tablets are characterized by a timed, that is, non-continuous printing process, as US 2007/0014852 A1 or WO 2006/058247 show. Usually, ink jet processes or pad printing processes are used. The printing inks used here usually contain waxes and / or fats or ingredients that increase the scratch resistance on the surfaces. This describes WO 2005/053599 A1.
Bei diesen genannten Anwendungen ist keine hohe Präzision der Druckfarbenmenge oder keine hohe Gleichmäßigkeit in der Druckfarbenübertragung auf das Substrat gefordert, welches darüber hinaus auch nicht mit einem getakteten Verfahren technisch möglich ist. In these applications, there is no high precision of ink quantity or high uniformity in ink transfer to the substrate which, moreover, is not technically possible with a clocked method.
Aus der DE 34 23 328 A1 ist als kontinuierliches Druckverfahren zur Übertragung von Klebstoffen, die Wirkstoffe enthalten können, das Tiefdruck- und das Siebdruckverfahren bekannt. From DE 34 23 328 A1 is known as a continuous printing process for the transfer of adhesives, which may contain active ingredients, the gravure and the screen printing process.
Ein weiteres Problem in der Herstellung von ODFs besteht darin, dass die zwingend erforderliche Kontrolle des Wirkstoffgehalts zumeist als zerstörerische Produktprüfung stattfindet, das heißt, der einzelne ODF wird bezüglich seiner Bestandteile analysiert und dabei der festgestellte Wirkstoffgehalt mit dem vorgegeben Wirkstoffgehalt vergleichen. Wird dabei eine Abweichung festgestellt, kann dies zum Verlust einer ganzen Charge führen. Another problem in the production of ODFs is that the mandatory control of the active ingredient content usually takes place as a destructive product test, that is, the individual ODF is analyzed for its constituents, comparing the detected active ingredient content with the predetermined active ingredient content. If a deviation is detected, this can lead to the loss of an entire batch.
Für den sparsamen Umgang mit Wirkstoffen ist daher erforderlich, dass die Kontrolle während des kontinuierlichen Herstellungsverfahren stattfindet und dass das Kontrollverfahren möglichst umgehend, am besten sofort ein Ergebnis liefert, um auf Abweichungen des Wirkstoffgehalts durch einen Stopp des Verfahrens unmittelbar reagieren zu können. Auf diese Weise ist gewährleistet, dass die Verluste an Wirkstoffen insgesamt deutlich reduziert werden.  It is therefore necessary for the sparing use of active ingredients that the control takes place during the continuous production process and that the control method should as soon as possible, preferably immediately produce a result in order to be able to react immediately to deviations of the active ingredient content by stopping the process. This ensures that the overall loss of active ingredients is significantly reduced.
Eine typische Zusammensetzung eines oralen Wirkstofffilms sieht aus wie folgt: A typical composition of an oral drug film looks like this:
• Pharmazeutisch wirksamer Wirkstoff 1 bis 30 Gew.-%  Pharmaceutically active ingredient 1 to 30% by weight
• Wasserlösliches Filmpolymer wie Pharmacoat oder Methocel (Hydroxyporpyl methylcellulose) 40 bis 50 Gew.-%  Water-soluble film polymer such as Pharmacoat or Methocel (hydroxyporpyl methylcellulose) 40 to 50% by weight
· Weichmacher wie Glycerol 0 bis 20 Gew.-%  Plasticizers such as glycerol 0 to 20% by weight
• Füllstoffe, Farbstoffe, Aromastoffe und weitere Zusätze 0 bis 40 Gew.-%  Fillers, dyes, flavorings and other additives 0 to 40% by weight
Im Übrigen sei auf den Artikel „Advances in orodisperible films for drug delivery" der Autoren Hoffmann, Breitenbach und Breitkreuz aus dem Fachjournal Expert Opinion on Drug Delivery - 03/18/1 1 verwiesen, der auch unter anderem, die typischen Inhaltsstoffe der Basisfilme auf Seite 303 beschreibt und ansonsten eine sehr gute Zusammenfassung über die Herstellung und Eigenschaften verschiedener oraler Wirkstofffilme darstellt. Aufgabe der Erfindung ist es, ein Verfahren zur Herstellung und Kontrolle von oralen Wirkstoff-Filmen anzugeben, das durch ein präzises Herstellungsverfahren und durch ein effektives Kontrollverfahren zu möglichst geringen Verlusten an Wirkstoffen führt und das Schwankungen im Wirkstoffgehalt in den oralen Wirkstoff-Filmen möglichst unterdrückt. In addition, the article "Advances in orodisperible films for drug delivery" by the authors Hoffmann, Breitenbach and Breitkreuz from the journal Expert Opinion on Drug Delivery - 03/18/1 1 referenced, which includes, among other things, the typical ingredients of the base films on Page 303 and otherwise provides a very good summary of the preparation and properties of various oral drug films. The object of the invention is to provide a process for the preparation and control of oral drug films, which leads by a precise manufacturing process and by an effective control method to the lowest possible loss of active ingredients and suppresses the variations in the active ingredient content in the oral drug films as possible.
Gelöst wird diese Aufgabe durch ein Verfahren, wie es im Hauptanspruch niedergelegt ist. Vorteilhafte Ausführungsformen des Verfahrens sind Gegenstand der Unteransprüche. This problem is solved by a method as laid down in the main claim. Advantageous embodiments of the method are the subject of the dependent claims.
Demgemäß betrifft die Erfindung ein Verfahren zur Herstellung und Kontrolle von oralen Wirkstoff-Filmen mit einer Basis, auf die eine zumindest einen Wirkstoff enthaltende Lösung aufgebracht wird, umfassend die Schritte: Accordingly, the invention relates to a process for the preparation and control of oral drug films with a base to which a solution containing at least one drug is applied, comprising the steps:
• Dosieren und Mischen der Basisrezeptur,  Dosing and mixing of the base formulation,
· Beschichtung der Basisrezeptur auf eine Unterlage, so dass sich eine Bahn ergibt,  Coating the base formulation on a base so that a web results,
• gegebenenfalls Trocknung der auf der Unterlage beschichteten Basisrezepturbahn,  If appropriate drying of the base recipe coated on the base,
• Aufdrucken einer zumindest einen Wirkstoff enthaltenden Farbstofflösung nach dem Flexod ruckverfahren auf der Oberseite der Basisrezepturbahn,  Printing of a dye solution containing at least one active substance by the flexographic printing process on the upper side of the base receiving web,
• Trocknung der auf der Unterlage beschichteten Basisrezepturbahn samt aufgedruckter Wirkstofflösung,  Drying of the base recipe web coated on the substrate together with printed drug solution,
• Durchstrahlen der auf der Unterlage beschichteten Basisrezepturbahn samt aufgedruckter Wirkstofflösung von der Ober- und/oder Unterseite mittels einer Strahlung aus einer Strahlungsquelle,  Irradiating the base receiving web coated on the base together with printed active substance solution from the upper and / or lower side by means of radiation from a radiation source,
• Messung der Transmission der durchgetretenen Strahlung auf der gegenüberliegenden Seite der auf der Unterlage beschichteten Basisrezepturbahn samt aufgedruckter Wirkstofflösung Überraschenderweise wurde gefunden, dass das eigentlich in der Verpackungsmittelindustrie eingesetzte Flexod ruckverfahren zur Übertragung von Arzneiwirkstoffen auf die Basisrezepturbahn die beste Herstellungsart ist.  Surprisingly, it has been found that the flexographic printing process actually used in the packaging industry for the transfer of active ingredients to the base formulation web is the best method of production.
Das Flexodruckverfahren ist ein kontinuierliches Druckverfahren, bietet die geforderte hohe Präzision und sichert die hohe Gleichmäßigkeit im Übertrag von Arzneiwirkstoffen auf die Basisrezepturbahn ab. Der einfache Aufbau eines Flexodruckwerks ermöglicht, mit geringsten Verlusten an Druckfarbenmengen einen prozesssicheren Beschichtungsprozess zu realisieren. Die Auftragsmenge kann durch unterschiedliche Auslegung der hoch präzisen Rasterwalze bestimmt werden und ermöglicht somit auch die sichere Gleichmäßigkeit der Auftragsmenge. The flexographic printing process is a continuous printing process, offers the required high precision and ensures the high uniformity in the transfer of active pharmaceutical ingredients on the base recipe train. The simple structure of a flexographic printing unit makes it possible to realize a process-reliable coating process with minimal losses of ink quantities. The order quantity can be determined by different design of the high-precision anilox roller and thus also enables the reliable uniformity of the order quantity.
Nach DIN 16514: 1982-1 1 ist der Flexodruck ein Verfahren des direkten Hochdrucks. Die Druckform ist aus Gummi oder elastischem photopolymerem Kunststoff. Die Einfärbung der Druckform erfolgt mittels einer geätzten oder gravierten Rasterwalze aus Stahl mit Verchromung oder Keramik (Chromoxid), deren Näpfchen direkt mit einer Kammerrakel oder einer Tauchwalze mit Druckfarbe gefüllt werden. Die überschüssige Farbe wird von der Rasterwalze mit einem Rakel abgerakelt oder (in älteren Maschinen) mit einer Gummiwalze abgequetscht. Die Druckgeschwindigkeit beträgt, je nach Art des Bedruckstoffes und Motivs, im Verpackungsdruck 100 bis 300 m/min. Haupteinsatzgebiet ist der Verpackungsdruck.  According to DIN 16514: 1982-1 1, flexographic printing is a process of direct high pressure. The printing form is made of rubber or elastic photopolymeric plastic. The inking of the printing plate by means of an etched or engraved anilox roller made of steel with chrome plating or ceramic (chromium oxide), the wells are filled directly with a chambered doctor blade or a fountain roller with ink. The excess ink is scraped from the anilox roller with a squeegee or squeezed (in older machines) with a rubber roller. Depending on the type of substrate and motif, the printing speed is 100 to 300 m / min in packaging printing. The main field of application is packaging printing.
Es können auch mehrere Flexod ruckwerke hintereinander angeordnet sein, um die Auftragsmenge entsprechend erhöhen zu können. It can also be arranged in succession Flexod jerkies in order to increase the order quantity accordingly.
Für diesen Fall ist es vorteilhaft, wenn nach jedem Druck eine Messung der Transmission durchgeführt wird.  For this case, it is advantageous if a measurement of the transmission is carried out after each pressure.
In einer alternativen Variante wird die bedruckte Basisrezepturbahn (nach der Messung) aufgewickelt und erneut dem einen Flexodruckwerk zugeführt. Dieser Vorgang kann mehrmals hintereinander durchgeführt werden, bis die gewünschte Menge an Wirkstoff aufgebracht ist. In an alternative variant, the printed base recipe web is wound up (after the measurement) and fed again to the one flexographic printing unit. This process can be carried out several times in succession until the desired amount of active ingredient has been applied.
Der Druck muss nicht vollflächig erfolgen, eine partielle Übertragung der zumindest einen Wirkstoff enthaltenden Farbstofflösung ist ebenfalls möglich.  The pressure does not have to be on the entire surface, a partial transfer of at least one drug-containing dye solution is also possible.
Üblicherweise liegt der Anteil an Wirkstoff(en) in der zumindest einen Wirkstoff enthaltenden Farbstoff lösung zwischen 0,01 und 25 Gew.-%, insbesondere 5 bis 15 Gew.-%. Der Wert von 25 Gew.-% kann aber auch - je nach Anforderung nach oben überschritten werden, falls es zur Erzielung des gewünschten Effektes notwendig ist.Usually, the proportion of active ingredient (s) in the at least one drug-containing dye solution is between 0.01 and 25 wt .-%, in particular 5 to 15 wt .-%. However, the value of 25% by weight may also be exceeded, depending on the requirements, if it is necessary to achieve the desired effect.
Der Anteil an Farbstoff(en) in der zumindest einen Wirkstoff enthaltenden Farbstofflösung beträgt 0,01 und 10 Gew.-%, insbesondere 1 bis 5 Gew.-%. Auch der Wert von 10 Gew.-% kann aber auch - je nach Anforderung nach oben überschritten werden, falls es zur Erzielung des gewünschten Effektes notwendig ist. Als Farbstoffe sollten nur solche eingesetzt werden, die in Arzneimitteln auch zugelassen sind. Derartige Farbstoffe finden sich beispielsweise in Listen wieder, die von der Food and Drug Administration (FDA) unter der Bezeichnung„Summary of Color Additives for Use in United States in Foods, Drugs, Cosmetics, and Medical Devices" herausgegeben werden. Unter diesen Farbstoffen seien namentlich erwähnt The proportion of dye (s) in the at least one drug-containing dye solution is 0.01 and 10 wt .-%, in particular 1 to 5 wt .-%. However, the value of 10% by weight may also be exceeded, depending on the requirements, if it is necessary to achieve the desired effect. Dyes should only be used as those which are also authorized in medicinal products. Such dyes can be found, for example, in lists published by the Food and Drug Administration (FDA) under the name "Summary of Color Additives for Use in United States in Foods, Drugs, Cosmetics, and Medical Devices." Among these dyes mentioned by name
• Brillantblau FCF oder E 133 • Brilliant blue FCF or E 133
(Dihydrogen(ethyl)[4-[4-[ethyl- (3-sulfonatobenzyl)]amino]-2'-sulfonato- benzhydryliden]-cyclohexa-2,5-dien- 1 -yliden]-(3-sulfonatobenzyl)ammonium, (Dihydrogen (ethyl) [4- [4- [ethyl- (3-sulfonatobenzyl)] amino] -2'-sulfonatobenzhydrylidene] -cyclohexa-2,5-dien-1-ylidene] - (3-sulfonatobenzyl) ammonium .
Dinatriumsalz) disodium salt)
• Indigokarmin oder E 132  • Indigo carmine or E 132
(lndigotin-5,5'-disulfonsäure Dinatriumsalz)  (Indigotin-5,5'-disulfonic acid disodium salt)
Die Trocknung der auf der Unterlage beschichteten Basisrezepturbahn samt aufgedruckter Wirkstofflösung erfolgt vorzugsweise kontinuierlich. Geeignete kontinuierliche Trocknungsverfahren sind unter anderem Heißlufttrocknung, Infrarot- Trocknung, Hochfrequenztrocknung und/oder Kombinationen aus allen Verfahren. Das Trocknungsprofil (Temperatur und Zeit) wird dabei so eingestellt, dass ein möglichst geringer Restlösungsmittelgehalt erreicht wird. Geeignete Temperaturen liegen zwischen 40 °C und 150 °C, geeignete Trocknungszeiten bei 1 bis 30 Minuten. The drying of the base receiving web coated on the base together with the printed active substance solution is preferably carried out continuously. Suitable continuous drying processes include hot air drying, infrared drying, high frequency drying and / or combinations of all processes. The drying profile (temperature and time) is adjusted so that the lowest possible residual solvent content is achieved. Suitable temperatures are between 40 ° C and 150 ° C, suitable drying times of 1 to 30 minutes.
Die Bestimmung des Wirkstoffgehalts wird erfindungsgemäß mittels einer Farbstoffzugabe in der wirkstoffhaltigen Druckfarbenlösung und einem physikalischen Transmissionsmessverfahrens realisiert. The determination of the active ingredient content is realized according to the invention by means of a dye addition in the active substance-containing printing ink solution and a physical transmission measuring method.
Mit der Transparenz beziehungsweise dem Transmissionsgrad - bisweilen auch nur kurz als Transmission bezeichnet -, der in der Regel in % angegeben wird, ist das Verhältnis der auf der Rückseite eines mit Licht durchstrahlten Körpers ankommenden Lichtleistung zu der auf der Vorderseite eintreffenden Lichtleistung gemeint. Die Transmission wird beschnitten durch Reflektion und Absorption.  With the transparency or transmittance - sometimes referred to as transmittance - which is usually given in%, the ratio of the incident on the back of a light-irradiated body light output is meant to the incident on the front light output. The transmission is trimmed by reflection and absorption.
Es gilt also: Transmissionsgrad = (1 - Reflektionsgrad - Absorptionsgrad).  The following applies: Transmittance = (1 - Reflectance - Absorptance).
Der Begriff der Transmission wird erfindungsgemäß dahingehend ausgeweitet, dass unabhängig von der verwendeten Strahlungsart der Verlust an Strahlung beim Durchgang durch die Basisrezepturschicht samt Färb- und Wirkstoffauftrag als Transmission bezeichnet wird. The term transmission is inventively extended to the effect that regardless of the type of radiation used, the loss of radiation during Passage through the base formulation layer together with color and active substance application is referred to as transmission.
Die Strahlungsquelle durchstrahlt die Basisrezepturbahn samt aufgedruckter farbiger Wirkstofflösung. Bei der Durchstrahlung treten Strahlungsverluste auf, die auf der gegenüberliegenden Seite der Bahn über einen entsprechenden Detektor festgestellt werden können. The radiation source radiates through the base recipe web, along with the printed colored drug solution. Radiation losses occur during transmission, which can be detected on the opposite side of the web via a corresponding detector.
Hierfür ist zunächst eine Nullmessung zu machen, das heißt, die mit der gewünschten Konzentration an Wirk- und Farbstoff bedruckte Basisrezepturbahn (vorsorglich sollte der tatsächliche Wirkstoffgehalt mit einem zweiten, anderen Messverfahren bestätigt werden), wird durchstrahlt und der Transmissionswert festgestellt.  For this purpose, a zero measurement is first to be made, that is to say, the base formulation track printed with the desired concentration of active dye and dye (as a precaution, the actual active substance content should be confirmed by a second, different measuring method) is irradiated and the transmission value determined.
Im weiteren Verfahren wird nun der aktuell gemessene Transmissionswert mit dem Nullwert verglichen. Bei Abweichungen des tatsächlichen Messwerts von der gewünschten Vorgabe kann unmittelbar reagiert werden, indem zum Beispiel das Verfahren gestoppt wird, um den Fehler abzustellen. Auf diese Weise werden die Verluste wirkungsvoll verringert. In the further method, the currently measured transmission value is compared with the zero value. If the actual measured value deviates from the desired specification, it is possible to react immediately, for example by stopping the method in order to stop the error. In this way, the losses are effectively reduced.
Gerade wenn sich der Transmissionswert kontinuierlich ändert, beispielsweise ständig zunimmt, was auf eine Reduktion des Wirk- und Farbstoffgehalts hinweist, aber der Wert noch innerhalb der Toleranzgrenzen liegt, kann durch eine entsprechende Reaktion, also der sofortigen Anpassung des Wirk- und Farbstoffgehalts, ein Verlust an Wirkstoffen sogar vollständig vermieden werden.  Especially when the transmission value changes continuously, for example constantly increasing, indicating a reduction in the active and dye content, but the value is still within the tolerance limits, by a corresponding reaction, ie the immediate adjustment of the active and dye content, a loss even completely avoided on active ingredients.
Beispielsweise kann in der wirkstoffhaltigen Druckfarbenlösung ein Farbstoff enthalten sein, der die Lichtstrahlung einer roten Lichtquelle absorbiert. Wird eine geringe Menge an Farbstoff, das heißt gleichzeitig Wirkstoff bedruckt, ist die Absorption des Lichts gering und eine größere Menge an Licht wird von einer Photozelle erfasst, als wenn eine hohe Farbstoff und somit Wirkstoffmenge bedruckt würde. Der Transmissionsgrad ist direkt abhängig von der Farbstoffmenge (damit einhergehend Wirkstoff menge) und damit ein direktes kontaktloses Prüfverfahren zur Bestimmung des Wirkstoffgehalts, ohne dass der Prüfkörper zerstört werden muss. For example, a dye which absorbs the light radiation of a red light source can be contained in the active substance-containing printing ink solution. If a small amount of dye, ie at the same time printed active substance, the absorption of light is low and a larger amount of light is detected by a photocell, as if a high dye and thus drug amount would be printed. The transmittance is directly dependent on the amount of dye (associated amount of active substance) and thus a direct contactless test method for determining the active ingredient content, without the test specimen must be destroyed.
Dies stellt auch eine bevorzugte Ausführungsform des Verfahrens dar, wenn also als Strahlung sichtbares Licht und als Empfangseinheit eine Photozelle verwendet werden. Vorzugsweise ist das Kontrollverfahren ein optisches Verfahren. Gemäß einer ersten Variante des Verfahrens werden nach der Beschichtung der Basisrezeptur auf eine Unterlage und der gegebenenfalls anschließenden Trocknung aus der sich ergebenden Bahn die einzelnen Abschnitte der oralen Wirkstoff-Filme möglichst verlustfrei gestanzt, und zwar entweder direkt vor dem Druckvorgang oder direkt nach dem Druckvorgang. This is also a preferred embodiment of the method, that is to say when a visible light is used as the radiation and a photocell is used as the receiving unit. Preferably, the control method is an optical method. According to a first variant of the method, the individual sections of the oral active substance films are punched as lossless as possible after the coating of the base formulation on a substrate and the subsequent drying from the resulting web, either directly before the printing process or directly after the printing process.
Gemäß einer zweiten Variante des Verfahrens werden nach Messung der Transmission der durchgetretenen Strahlung aus der Basisrezepturbahn die einzelnen Abschnitte der oralen Wirkstoff-Filme möglichst verlustfrei gestanzt. According to a second variant of the method, after measuring the transmission of the transmitted radiation from the base receptor track, the individual sections of the oral active substance films are punched as loss-free as possible.
Vorteilhafterweise besteht die Stanzvorrichtung aus einer rotativen Schneidwalze und einer gleichläufigen Gegenwalze, wobei die Basisrezepturbahn in den Spalt zwischen der Schneidwalze und der Gegenwalze geführt wird. Vorteilhafterweise befindet sich die Basisrezepturbahn auf einer Trennfolie, die über die Gegenwalze geführt wird. In dem Spalt werden dann die einzelnen Konturen der Stanzlinge vorzugsweise ohne Stanzgitter in der Bahn durchgestanzt, möglichst ohne die Trennfolie zu verletzen (dieses Verfahren ist unter dem Namen kiss-cut-Verfahren bekannt und zeichnet sich dadurch aus, dass beim Stanzen die Trennfolie nicht oder nur unwesentlich verletzt beziehungsweise angestanzt wird). Advantageously, the punching device consists of a rotary cutting roller and a counter-rotating counter-rotating roller, wherein the base receiving track is guided into the gap between the cutting roller and the counter-roller. Advantageously, the base receiving web is located on a release film, which is guided over the counter roll. In the gap then the individual contours of the punched pieces are preferably punched through without punched grid in the web, if possible without violating the release film (this method is known under the name kiss-cut method and is characterized in that when punching the release film or not only marginally injured or punched).
Weiterhin bevorzugt besteht die Stanzvorrichtung aus einer Hub- oder Flachstanze, in die die Basisrezepturbahn gefördert wird. Vor der Hubstanze kann ein Pendeleinzug und/oder hinter der Hubstanze kann ein Puffer vorgesehen sein, um trotz der getackteten und damit eigentlich diskontinuierlichen Arbeitsweise der Hubstanze einen kontinuierlichen Fortgang des Verfahrens sicherzustellen. Further preferably, the punching device consists of a lifting or flat punch, in which the base receiving track is conveyed. Before the Hubstanze can be a shuttle and / or behind the Hubstanze a buffer may be provided to ensure a continuous progress of the process despite the bagged and thus actually discontinuous operation of the Hubstanze.
Abschließend werden vorteilhafterweise die einzelnen Abschnitte der oralen Wirkstoff- Filme in einen Beutel luft- und wasserdicht eingesiegelt. Finally, the individual sections of the oral drug films are advantageously air-tight and watertight sealed in a bag.
Gemäß einer bevorzugten Ausführungsform der Erfindung werden als Strahlung Infrarotstrahlung, sichtbares Licht, Ultraviolettstrahlung und/oder radioaktive Strahlung verwendet. Die Erfindung ist aber nicht auf die genannten Strahlungsquellen eingeschränkt, auch andere sind hierfür geeignet. According to a preferred embodiment of the invention are as radiation infrared radiation, visible light, ultraviolet radiation and / or radioactive radiation used. The invention is not limited to the radiation sources mentioned, others are suitable for this purpose.
Es können - je nach Breite der Bahn - neben einem auch zwei oder mehr Strahlungsempfänger eingesetzt werden. In einer Variante des Verfahrens pendelt der der Strahlungsempfänger insbesondere in Querrichtung der Basisrezepturbahn. Depending on the width of the web, it is possible to use two or more radiation receivers in addition to one. In a variant of the method, the radiation receiver oscillates in particular in the transverse direction of the base reception track.
Gemäß einer bevorzugten Variante wird die Basisrezepturbahn auf eine Trägerfolie als Unterlage, vorzugsweise aus Polyethylen, beschichtet, die zusammen mit der Basisrezepturbahn durch das Verfahren geführt wird. Besonders bevorzugt wird als Unterlage eine Folie aus Polyester, ganz besonders vorzugsweise aus Polyethylenterephthalat (PET). According to a preferred variant, the base receiving web is coated on a carrier film as backing, preferably made of polyethylene, which is guided through the process together with the base receiving web. Particularly preferred as backing is a film of polyester, most preferably of polyethylene terephthalate (PET).
Die Dicke der Trennfolie liegt insbesondere zwischen 60 und 150 μηη. Die Dicke der Basisrezepturbahn liegt üblicherweise zwischen 25 bis 200 μηη, insbesondere zwischen 65 bis 100 μηη.  The thickness of the release film is in particular between 60 and 150 μηη. The thickness of the base receiving web is usually between 25 and 200 μm, in particular between 65 and 100 μm.
Die Breite der Basisrezepturbahn ist bevorzugt zwischen 20 und 35 mm, 30 mm sind besonders vorteilhaft. The width of the base receiving track is preferably between 20 and 35 mm, 30 mm are particularly advantageous.
Vorzugsweise wird das Verfahren kontinuierlich in einem Arbeitsgang durchgeführt. Preferably, the process is carried out continuously in one operation.
Es ist aber auch möglich, nach der Beschichtung der Basisrezeptur auf die Unterlage, vorzugsweise Trennfolie und der sich gegebenenfalls anschließenden Trocknung der Basisrezepturbahn das Verfahren dahingehend zu unterbrechen, dass die Basisrezepturbahn zunächst zu Rollen aufgewickelt wird, beispielsweise mit Längen von 300 m bis 500 m. But it is also possible, after coating the base formulation on the substrate, preferably release film and optionally subsequent drying of the base formulation web the process to the effect that the base recipe web is first wound into rolls, for example with lengths of 300 m to 500 m.
Diese Rollen können dann gelagert oder an einen Weiterverarbeiter geliefert werden. Bei Bedarf werden die Rollen abgewickelt, und das erfindungsgemäße Verfahren beginnt mit dem Aufdrucken einer zumindest einen Wirkstoff enthaltenden Farbstofflösung nach dem Flexod ruckverfahren auf der Oberseite der Basisrezepturbahn.  These rolls can then be stored or delivered to a processor. If necessary, the rolls are unwound, and the inventive method begins with the printing of a dye solution containing at least one active substance by the Flexod jerk process on the top of the base formulation web.
Typische Wirkstoffe sind - ohne den Anspruch der Vollständigkeit im Rahmen der vorliegenden Erfindung zu erheben: Antiallergica, Antiarrhythmica, Antibiotica, Antidiabetica, Antiepileptica, Antihistaminica, Antitussiva, Cardiotonica, Diuretica, Hypotensiva, Narcotica, Neuro-Muskelblocker, Sexualhormone sowie Vasopressoren. Diese können je nach therapeutisch gewünschtem Ergebnis auch in Mischungen eingesetzt werden. Typical active ingredients are - without the claim of completeness to be raised in the context of the present invention: Antiallergic, antiarrhythmic, antibiotic, antidiabetic, antiepileptic, antihistaminic, antitussive, cardiotonic, diuretic, hypotensive, narcotic, neuro-muscular, sex hormones and vasopressors. These can also be used in mixtures depending on the therapeutically desired result.
Als Wirkstoffe können darüber hinaus erfindungsgemäß die aus Mundhygienestreifen bekannte Substanz Menthol eingesetzt werden, daneben auch andere Geschmacks-, Aroma- oder Duftstoffe, wie sie im Bereich der Mundhygiene verwendet werden. In addition, according to the invention, the substances menthol known from oral hygiene strips can be used according to the invention as active ingredients, as well as other flavorings, flavors or fragrances, as used in the field of oral hygiene.
Typische Polymere zur Bildung des Basisrezepturfilms sind Cellulosederivate wie Hydroxypropylmethylcellulose, Hydroxyethylcellulose und/oder Hydroxypropylcellulose sowie Maltodextrin. Die Polymere können dabei einzeln oder in beliebigen Mischungen eingesetzt werden. Typical polymers for forming the base formulation film are cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose and / or hydroxypropylcellulose and maltodextrin. The polymers can be used individually or in any mixtures.
Als Strahlungsquellen können Lichtquellen, die in dem gewünschten Wellenlängenbereich emittieren eingesetzt werden. Daneben kommen auch radioaktive Strahler zur Verwendung. As radiation sources light sources that emit in the desired wavelength range can be used. In addition, radioactive lamps are also used.
Als Empfangseinheit dienen Photozellen. Bei radioaktiver Strahlung genügen ein oder mehrere Geigerzähler zur Detektion der Strahlung. As a receiving unit serve photocells. With radioactive radiation, one or more Geiger counters suffice to detect the radiation.
Durch die Kombination des sehr präzisen und zuverlässigen Flexodruckverfahrens mit dem inline-Messverfahren, das ein sofortiges Ergebnis liefert, vermeidet die Erfindung übermäßige Verluste an Wirkstoff und die daraus resultierenden aufwändigen Reinigungs- sowie Entsorgungsarbeiten bei Fehlproduktionen sowie die Zwischenproduktkontrollen, By combining the very precise and reliable flexographic printing process with the in-line measurement method, which provides an immediate result, the invention avoids excessive losses of active ingredient and the resulting complex cleaning and disposal work in case of defective production and the intermediate controls,
Zusammenfassend hat das Verfahren einen einfachen und kompakten Maschinenaufbau und ermöglicht eine schnelle Umrüstung auf andere arzneimittelhaltige Druckfarben, wobei eine Cross-Kontamination unterschiedlicher Wirkstoffe vermieden werden kann. Je später im laufenden Verfahren der wertvolle Wirkstoff aufgebracht wird, umso geringer sind die Verluste desselben für den Fall, dass die Konzentration vom vorgegeben Wert abweicht.  In summary, the process has a simple and compact machine structure and allows rapid conversion to other drug-containing inks, whereby a cross-contamination of different active ingredients can be avoided. The later in the current process the valuable active substance is applied, the lower the losses of the same in the event that the concentration deviates from the predetermined value.
Aufgrund der sehr vorteilhaften Kombination des Flexodrucks mit der inline-Messung können Verarbeitungsgeschwindigkeiten von bis zu 100 m/min realisiert werden. Im Folgenden wird die Erfindung mittels eines Beispiels näher erläutert, ohne jegliche Einschränkung der Erfindung beabsichtigen zu wollen. Due to the very advantageous combination of flexographic printing with inline measurement, processing speeds of up to 100 m / min can be achieved. In the following, the invention is explained in more detail by means of an example, without intending to be bound by the invention.
Beispiel example
Eine Flexodruckmaschine wurde mit einer verchromten Rasterwalze ausgerüstet, deren Rasterweite 54 Linien pro cm, deren Näpchentiefe 40 μηη und deren theoretisches Schöpfvolumen 1 1 ,7 cm3/m2 beträgt. Als Druckzylinder wurde eine mit EPDM beschichtete Gummiwalze eingesetzt. Ein Gegendruckzylinder bildet mit dem Druckzylinder einen Walzenspalt, in dem der Druck nach der dem Fachmann bekannten Art des Flexodrucks erfolgt. Die Basisrezepturbahn, die über den Gegendruckzylinder in den Walzenspalt geführt wurde, war eine ODF-Basisfilmmaterialrolle in 20 mm Breite und 100 m Länge, deren Hauptbestandteil Hydroxypropylmethylcellulose ist. A flexographic printing machine was equipped with a chromium-plated anilox roller, the screen ruling 54 lines per cm, the depth of which is 40 μηη and their theoretical Schöpfvolumen 1 1, 7 cm 3 / m 2 . The printing cylinder used was an EPDM-coated rubber roller. An impression cylinder forms with the impression cylinder a nip in which the printing takes place according to the type of flexographic printing known to the person skilled in the art. The base recipe web fed into the nip via the impression cylinder was an ODF base film roll 20 mm wide and 100 m long, whose major component is hydroxypropylmethyl cellulose.
Die Druckfarbenlösung bestehend aus 4,4 Gew.-% Hydroxypropylcellulose, 8,9 Gew.-% Arzneiwirkstoff, 2,3 Gew.-% blauem Farbstoff und 84,4 Gew.-% Ethanol wird mit einer Druckgeschwindigkeit von 15 m/min auf die Basisrezepturbahn bedruckt.  The printing ink solution consisting of 4.4% by weight of hydroxypropylcellulose, 8.9% by weight of active substance, 2.3% by weight of blue dye and 84.4% by weight of ethanol is applied at a printing speed of 15 m / min printed on the base recipe track.
Nach dem Druckwerk folgt eine Trocknereinheit, bei der über Konvektionstrocknung das Lösemittel in Form von Ethanol verdampft. Anschließend wird das bedruckte Band zu einer Rolle aufgewickelt und wird - ohne das Flexod ruckwerk umzurüsten dreimal hintereinander bedruckt. The printing unit is followed by a dryer unit in which the solvent is evaporated in the form of ethanol by convection drying. The printed ribbon is then wound into a roll and printed three times in succession without retooling the flexo.
Die ermittelten Transmissionsmesswerte der mit der einen Wirkstoff enthaltenen Farblösung oberseitig bedruckten Basisrezepturbahn wurden mit einer roten Leuchtdiode (= Wellenlänge 650 nm) - wie in Figur 1 dargestellt - gemessen und betrugen: The measured transmission measured values of the base formulation printed on the top side with the dye solution containing one active substance were measured and measured with a red light-emitting diode (= wavelength 650 nm) as shown in FIG.
Ohne Bedruckung = Nullwert = 80,9 % Without printing = zero value = 80.9%
1 x bedruckt: 74,7 % Printed 1 x 74.7%
2x bedruckt: 64,7 % 2x printed: 64.7%
3x bedruckt: 56,7 % Die durch ein chemisches Analyseverfahren ermittelte Menge an Arzneiwirkstoff auf der Basisrezepturbahn betrug: 3x printed: 56.7% The amount of drug on the base formulation track determined by a chemical analysis procedure was:
Ohne Bedruckung = Nullwert = 0,00 mg / 6 cm2 Without printing = zero value = 0.00 mg / 6 cm 2
1 x bedruckt: 0,34 mg / 6 cm2 1 x printed: 0.34 mg / 6 cm 2
2x bedruckt: 0,63 mg / 6 cm2 2x printed: 0.63 mg / 6 cm 2
3x bedruckt: 0,87 mg / 6 cm2 3x printed: 0.87 mg / 6 cm 2
Wie zu erkennen ist, nimmt der Transmissionswert mit Zunahme der Farbstoff- und damit einhergehend der Wirkstoffkonzentration ab. As can be seen, the transmission value decreases with an increase in the colorant and concomitantly the active ingredient concentration.
Für eine vorgegebene Konzentration wird der Transmissionswert bestimmt. Abweichungen von diesem außerhalb der vorgegebenen Fehlertoleranzen werden inline und somit sofort festgestellt, so dass ein Eingriff in das Verfahren schnellstmöglich erfolgen kann. For a given concentration, the transmission value is determined. Deviations from this outside the specified error tolerances are determined inline and thus immediately, so that an intervention in the process can be carried out as quickly as possible.
Bezugszeichenliste Rote LED-Lichtquelle REFERENCE SYMBOL Red LED light source
Photozelle (Empfänger) Photocell (receiver)
OP-Verstärker OP amplifier
Anzeige des Transmissionswertes Display of the transmission value

Claims

1 1
Patentansprüche claims
Verfahren zur Herstellung und Kontrolle von oralen Wirkstoff-Filmen mit einer Basis, auf die eine zumindest einen Wirkstoff enthaltende Lösung aufgebracht wird, umfassend die Schritte: A process for preparing and controlling oral drug films having a base to which a solution containing at least one drug is applied, comprising the steps of:
• Dosieren und Mischen der Basisrezeptur,  Dosing and mixing of the base formulation,
• Beschichtung der Basisrezeptur auf eine Unterlage, so dass sich eine Bahn ergibt  • coating the base formulation on a base to form a sheet
• gegebenenfalls Trocknung der auf der Unterlage beschichteten Basisrezepturbahn,  If appropriate drying of the base recipe coated on the base,
• Aufdrucken einer zumindest einen Wirkstoff enthaltenden Farbstofflösung nach dem Flexod ruckverfahren auf der Oberseite der Basisrezepturbahn, Printing of a dye solution containing at least one active substance by the flexographic printing process on the upper side of the base receiving web,
• Trocknung der auf der Unterlage beschichteten Basisrezepturbahn samt aufgedruckter Wirkstofflösung, Drying of the base recipe web coated on the substrate together with printed drug solution,
• Durchstrahlen der auf der Unterlage beschichteten Basisrezepturbahn samt aufgedruckter Wirkstofflösung von der Ober- und/oder Unterseite mittels einer Strahlung aus einer Strahlungsquelle,  Irradiating the base receiving web coated on the base together with printed active substance solution from the upper and / or lower side by means of radiation from a radiation source,
• Messung der Transmission der durchgetretenen Strahlung auf der gegenüberliegenden Seite der auf der Unterlage beschichteten Basisrezepturbahn samt aufgedruckter Wirkstofflösung mittels mindestens einer Empfangseinheit.  Measurement of the transmission of the transmitted radiation on the opposite side of the base receiving track coated on the base together with printed active substance solution by means of at least one receiving unit.
Verfahren nach Anspruch 1 , Method according to claim 1,
dadurch gekennzeichnet, dass characterized in that
nach der Beschichtung der Basisrezeptur auf eine Unterlage und der gegebenenfalls anschließenden Trocknung aus der sich ergebenden Bahn die einzelnen Abschnitte der oralen Wirkstoff-Filme gestanzt werden, und zwar entweder direkt vor dem Druckvorgang oder direkt nach dem Druckvorgang. after coating the base formulation on a backing and optionally subsequently drying it from the resulting web, the individual sections of the oral drug films are punched, either directly prior to printing or immediately after printing.
Verfahren nach Anspruch 1 , Method according to claim 1,
dadurch gekennzeichnet, dass characterized in that
nach Messung der Transmission der durchgetretenen Strahlung aus der Basisrezepturbahn die einzelnen Abschnitte der oralen Wirkstoff-Filme gestanzt werden. after measuring the transmission of the transmitted radiation from the base receptor track, the individual sections of the oral drug films are punched.
4. Verfahren nach mindestens einem der Ansprüche 1 bis 3, 4. The method according to at least one of claims 1 to 3,
dadurch gekennzeichnet, dass  characterized in that
die einzelnen Abschnitte der oralen Wirkstoff-Filme abschließend in einen Beutel eingesiegelt werden.  the individual sections of the oral drug films are finally sealed in a bag.
5. Verfahren nach mindestens einem der vorherigen Ansprüche, 5. The method according to at least one of the preceding claims,
dadurch gekennzeichnet, dass  characterized in that
als Strahlung Infrarotstrahlung, sichtbares Licht, Ultraviolettstrahlung und/oder radioaktive Strahlung verwendet wird.  as radiation infrared radiation, visible light, ultraviolet radiation and / or radioactive radiation is used.
6. Verfahren nach mindestens einem der vorherigen Ansprüche, 6. The method according to at least one of the preceding claims,
dadurch gekennzeichnet, dass  characterized in that
als Strahlung sichtbares Licht und als Empfangseinheit eine Photozelle verwendet werden.  as radiation visible light and as a receiving unit a photocell can be used.
7. Verfahren nach mindestens einem der vorherigen Ansprüche, 7. The method according to at least one of the preceding claims,
dadurch gekennzeichnet, dass  characterized in that
die Basisrezepturbahn auf eine Trennfolie beschichtet wird.  the base recipe web is coated on a release film.
8. Verfahren nach mindestens einem der vorherigen Ansprüche, 8. The method according to at least one of the preceding claims,
dadurch gekennzeichnet, dass  characterized in that
die Dicke der Basisrezepturbahn zwischen 25 bis 200 μηη, insbesondere zwischen 65 bis 100 m liegt.  the thickness of the base reception track is between 25 and 200 μm, in particular between 65 and 100 m.
9. Verfahren nach mindestens einem der vorherigen Ansprüche, 9. The method according to at least one of the preceding claims,
dadurch gekennzeichnet, dass  characterized in that
das Verfahren kontinuierlich durchgeführt wird.  the process is carried out continuously.
EP12735126.0A 2011-08-12 2012-07-09 Method for producing and monitoring oral active ingredient films Not-in-force EP2741734B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102011080870 2011-08-12
DE102011088909A DE102011088909A1 (en) 2011-08-12 2011-12-16 Process for the preparation and control of oral drug films
PCT/EP2012/063405 WO2013023841A1 (en) 2011-08-12 2012-07-09 Method for producing and monitoring oral active ingredient films

Publications (2)

Publication Number Publication Date
EP2741734A1 true EP2741734A1 (en) 2014-06-18
EP2741734B1 EP2741734B1 (en) 2016-03-09

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Application Number Title Priority Date Filing Date
EP12735126.0A Not-in-force EP2741734B1 (en) 2011-08-12 2012-07-09 Method for producing and monitoring oral active ingredient films

Country Status (5)

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US (1) US9539206B2 (en)
EP (1) EP2741734B1 (en)
DE (1) DE102011088909A1 (en)
ES (1) ES2574478T3 (en)
WO (1) WO2013023841A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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JP7365409B2 (en) 2018-06-28 2023-10-19 エイアールエックス エルエルシー Dispensing method for producing soluble unit dose membrane constructs
FR3087125B1 (en) * 2018-10-11 2021-07-02 Ferring Bv METHOD OF MANUFACTURING A SOLID FORMULATION FOR ORAL ADMINISTRATION, ASSOCIATED INSTALLATION AND SOLID FORMULATION

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Also Published As

Publication number Publication date
WO2013023841A1 (en) 2013-02-21
US20140272099A1 (en) 2014-09-18
US9539206B2 (en) 2017-01-10
DE102011088909A1 (en) 2013-02-14
EP2741734B1 (en) 2016-03-09
ES2574478T3 (en) 2016-06-20

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